The Immune System: Innate and Adaptive Body Defenses: Part B

1. The Immune System: Innate and Adaptive Body Defenses: Part B

2. Adaptive Defenses • Adaptive immune response • Is specific • Is systemic • Has memory • Two separate overlapping arms • Humoral (antibody-mediated) immunity • Cellular (cell-mediated) immunity

3. Antigens • Substances that can mobilize the adaptive defenses and provoke an immune response • Most are large, complex molecules not normally found in the body (nonself)

4. Complete vs. incomplete Antigens Complete Antigens Incomplete Antigens • Important functional properties • Immunogenicity: ability to stimulate proliferation of specific lymphocytes and antibodies • Reactivity: ability to react with products of activated lymphocytes and antibodies released • Examples: foreign protein, polysaccharides, lipids, and nucleic acids • Called Haptens • Small molecules (peptides, nucleotides, and hormones) • Not immunogenic by themselves • Are immunogenic when attached to body proteins • Cause the immune system to mount a harmful attack • Examples: poison ivy, animal dander, detergents, and cosmetics

5. Antigenic Determinants • Certain parts of an entire antigen that are immunogenic • Antibodies and lymphocyte receptors bind to them • Most naturally occurring antigens have numerous antigenic determinants that • Mobilize several different lymphocyte populations • Form different kinds of antibodies against it • Large, chemically simple molecules (e.g., plastics) have little or no immunogenicity

6. Antigen- binding sites Antigenic determinants Antibody A Antigen Antibody B Antibody C Figure 20.7

7. Self-Antigens: MHC Proteins • Protein molecules (self-antigens) on the surface of cells • Antigenic to others in transfusions or grafts • Example: MHC proteins • Coded for by genes of the major histocompatibility complex (MHC) and are unique to an individual • Class I MHC are found on all body cells • Class II MHC are found only on certain cells that act in immune response • In the MHC is a groove where the cell displays a peptide usually from broken down cellular proteins ***this peptide CAN come from fragments of foreign antigens

8. Cells of the Adaptive Immune System • Two types of lymphocytes • B lymphocytes (B cells)—humoral immunity • T lymphocytes (T cells)—cell-mediated immunity • Antigen-presenting cells (APCs) • Do not respond to specific antigens • Play essential auxiliary roles in immunity

9. Lymphocytes • Originate in red bone marrow • B cells mature in the red bone marrow • T cells mature in the thymus • When mature, they have • Immunocompetence; they are able to recognize and bind to a specific antigen • Self-tolerance – unresponsive to self antigens • Naive (unexposed) B and T cells are exported to lymph nodes, spleen, and other lymphoid organs

10. Red bone marrow: site of lymphocyte origin Humoral immunity Adaptive defenses Cellular immunity Primary lymphoid organs: site of development of immunocompetence as B or T cells Immature lymphocytes Red bone marrow Secondary lymphoid organs: site of antigen encounter, and activation to become effector and memory B or T cells 1 Lymphocytes destined to become T cells migrate (in blood) to the thymus and develop immunocompetence there. B cells develop immunocompetence in red bone marrow. Thymus Bone marrow 2 Immunocompetent but still naive lymphocytes leave the thymus and bone marrow. They “seed” the lymph nodes, spleen, and other lymphoid tissues where they encounter their antigen. Lymph nodes, spleen, and other lymphoid tissues 3 Antigen-activated immunocompetent lymphocytes (effector cells and memory cells) circulate continuously in the bloodstream and lymph and throughout the lymphoid organs of the body. Figure 20.8

11. T Cells • T cells mature in the thymus under negative and positive selection pressures • Positive selection • Selects T cells capable of binding to self-MHC proteins (MHC restriction) • Negative selection • Prompts apoptosis of T cells that bind to self-antigens displayed by self-MHC • Ensures self-tolerance

12. Adaptive defenses Cellular immunity Positive selection: T cells must recognize self major histocompatibility proteins (self-MHC). Antigen- presenting thymic cell Developing T cell Failure to recognize self-MHC results in apoptosis(death by cell suicide). MHC T cell receptor Self-antigen Recognizing self-MHC results in MHCrestriction—survivors are restricted to recognizing antigen on self-MHC. Survivors proceed to negative selection. Negativeselection: T cellsmust notrecognize self-antigens. Recognizing self-antigen results in apoptosis. This eliminates self-reactive T cells that could cause autoimmune diseases. Failure to recognize (bind tightly to) self-antigen results in survival and continued maturation. Figure 20.9

13. B Cells • B cells mature in red bone marrow • Self-reactive B cells • Are eliminated by apoptosis (clonal deletion) or • Undergo receptor editing – rearrangement of their receptors • Are inactivated (anergy) if they escape from the bone marrow

14. Antigen Receptor Diversity • Lymphocytes make up to a billion different types of antigen receptors • Coded for by ~25,000 genes • Gene segments are shuffled by somatic recombination • Genes determine which foreign substances the immune system will recognize and resist NOT the antigen!!!!

15. Antigen-Presenting Cells (APCs) • Engulf antigens • Present fragments of antigens to be recognized by T cells • Major types • Dendritic cells in connective tissues and epidermis • Macrophages in connective tissues and lymphoid organs • B cells

16. Figure 20.10

17. Macrophages and Dendritic Cells • Present antigens and activate T cells • Macrophages mostly remain fixed in the lymphoid organs • Dendritic cells internalize pathogens and enter lymphatics to present the antigens to T cells in lymphoid organs • Activated T cells release chemicals that • Prod macrophages to become insatiable phagocytes and to secrete bactericidal chemicals

18. Adaptive Immunity: Summary • Uses lymphocytes, APCs, and specific molecules to identify and destroy nonself substances • Depends upon the ability of its cells to • Recognize antigens by binding to them • Communicate with one another so that the whole system mounts a specific response

19. Humoral Immunity Response • Antigen challenge • First encounter between an antigen and a naive immunocompetent lymphocyte • Usually occurs in the spleen or a lymph node • If the lymphocyte is a B cell • The antigen provokes a humoral immune response • Antibodies are produced

20. Clonal Selection • B cell is activated when antigens bind to its surface receptors and cross-link them • Receptor-mediated endocytosis of cross-linked antigen-receptor complexes occurs • Stimulated B cell grows to form a clone of identical cells bearing the same antigen-specific receptors(T helper cells are usually required to help B cells achieve full activation)

21. Fate of the Clones • Most clone cells become plasma cells • secrete specific antibodies at the rate of 2000 molecules per second for four to five days • Secreted antibodies • Circulate in blood or lymph • Bind to free antigens • Mark the antigens for destruction • Clone cells that do not become plasma cells become memory cells • Provide immunological memory • Mount an immediate response to future exposures of the same antigen

22. Fate of the Clones • Clone cells that do not become plasma cells become memory cells • Provide immunological memory • Mount an immediate response to future exposures of the same antigen • Memory cells allow the secondary immune response to be faster, more prolonged and more effective than primary immune response. (antibodies can peak in 2-3 days instead of the nearly 10 days in first response lag time)

23. Adaptive defenses Humoral immunity Antigen Primary response (initial encounter with antigen) Antigen binding to a receptor on a specific B lymphocyte (B lymphocytes with non-complementary receptors remain inactive) Proliferation to form a clone Activated B cells Plasma cells (effector B cells) Memory B cell— primed to respond to same antigen Secreted antibody molecules Figure 20.11 (1 of 2)

24. Immunological Memory • Primary immune response • Occurs on the first exposure to a specific antigen • Lag period: three to six days • Peak levels of plasma antibody are reached in 10 days • Antibody levels then decline

25. Humoral immunity Active Passive Naturally acquired Naturally acquired Artificially acquired Artificially acquired Infection; contact with pathogen Antibodies pass from mother to fetus via placenta; or to infant in her milk Vaccine; dead or attenuated pathogens Injection of immune serum (gamma globulin) Figure 20.13

26. Antibodies • Immunoglobulins—gamma globulin portion of blood • Proteins secreted by plasma cells • Capable of binding specifically with antigen detected by B cells

27. Basic Antibody Structure • T-or Y-shaped monomer of four looping linked polypeptide chains • Two identical heavy (H) chains and two identical light (L) chains • Variable (V) regions of each arm combine to form two identical antigen-binding sites • Constant (C) region of stem determines • The antibody class (IgM, IgA, IgD, IgG, or IgE) • The cells and chemicals that the antibody can bind to • How the antibody class functions in antigen elimination

28. Antigen-binding site Heavy chain variable region Hinge region Heavy chain constant region Stem region Light chain variable region Light chain constant region Disulfide bond (a) Figure 20.14a

29. Antibodies: type/ location/ function/ unique traits

30. Classes of Antibodies • IgM • A pentamer; first antibody released • Potent agglutinating agent • Readily fixes and activates complement • IgA (secretory IgA) • Monomer or dimer; in mucus and other secretions • Helps prevent entry of pathogens

31. Table 20.3

32. Classes of Antibodies • IgD • Monomer attached to the surface of B cells • Functions as a B cell receptor • IgG • Monomer; 75–85% of antibodies in plasma • From secondary and late primary responses • Crosses the placental barrier • IgE • Monomer active in some allergies and parasitic infections • Causes mast cells and basophils to release histamine

33. Table 20.3

34. Generating Antibody Diversity • Billions of antibodies result from somatic recombination of gene segments • Hypervariable regions of some genes increase antibody variation through somatic mutations • Each plasma cell can switch the type of H chain produced, making an antibody of a different class

35. Antibody Targets • Antibodies inactivate and tag antigens • Form antigen-antibody (immune) complexes • Defensive mechanisms used by antibodies • PLAN= precipitation/ lysis by complement/ agglutination/ neutralization • Neutralization and agglutination (the two most important) • Precipitation is similar to agglutination • Complement fixation we have discussed earlier and is the chief antibody defense against cellular antigens such as bacteria/ foreign red blood cells

36. Neutralization • Simplest mechanism • Antibodies block specific sites on viruses or bacterial exotoxins • Prevent these antigens from binding to receptors on tissue cells • Antigen-antibody complexes undergo phagocytosis

37. Agglutination • Antibodies bind the same determinant on more than one cell-bound antigen • Cross-linked antigen-antibody complexes agglutinate • Example: clumping of mismatched blood cells

38. Precipitation • Soluble molecules are cross-linked • Complexes precipitate and are subject to phagocytosis

39. Complement Fixation and Activation • Main antibody defense against cellular antigens • Several antibodies bind close together on a cellular antigen • Their complement-binding sites trigger complement fixation into the cell’s surface • Complement triggers cell lysis • Activated complement functions • Amplifies the inflammatory response • Opsonization • Enlists more and more defensive elements

40. Adaptive defenses Humoral immunity Antigen-antibody complex Antigen Antibody Inactivates by Fixes and activates Neutralization (masks dangerous parts of bacterial exotoxins; viruses) Agglutination (cell-bound antigens) Precipitation (soluble antigens) Complement Enhances Enhances Leads to Inflammation Phagocytosis Cell lysis Chemotaxis Histamine release Figure 20.15

41. Cell-Mediated Immune Response • As opposed to Humoral Immune Response where the antibodies attach to obvious antigens and mark them for destruction, cell-mediated immune response finds the hidden pathogens and then directly attacks. • T cells provide defense against intracellular antigens • Two types of surface receptors of T cells • T cell antigen receptors (MHC) • Cell differentiation glycoproteins • CD4 or CD8 • Play a role in T cell interactions with other cells

42. Cell-Mediated Immune Response • Major types of T cells • CD4 cells become helper T cells (TH) when activated • CD8 cells become cytotoxic T cells (TC) that destroy cells harboring foreign antigens • Other types of T cells • Regulatory T cells (TREG) • Memory T cells

43. Adaptive defenses Cellular immunity Immature lymphocyte Red bone marrow T cell receptor T cell receptor Maturation Class I MHC protein Class II MHC protein CD4 cell CD8 cell Thymus Activation Activation APC (dendritic cell) Memory cells APC (dendritic cell) CD4 CD8 Lymphoid tissues and organs Effector cells Helper T cells (or regulatory T cells) Cytotoxic T cells Blood plasma Figure 20.16

44. Comparison of Humoral and Cell-Mediated Response • Antibodies of the humoral response • The simplest ammunition of the immune response • Targets • Bacteria and molecules in extracellular environments (body secretions, tissue fluid, blood, and lymph) • T cells of the cell-mediated response • Recognize and respond only to processed fragments of antigen displayed on the surface of body cells • Targets • Body cells infected by viruses or bacteria • Abnormal or cancerous cells • Cells of infused or transplanted foreign tissue

45. Monoclonal Antibodies • Commercially prepared pure antibody • Produced by hybridomas • Cell hybrids: fusion of a tumor cell and a B cell • Proliferate indefinitely and have the ability to produce a single type of antibody • Used in research, clinical testing, and cancer treatment • Attach to cancer cells and induce immune response • Also used to treat rheumatoid arthritis, Crohn’s disease, ulcerative colitis, prevention of kidney transplant rejections, and severe allergic asthma

46. Antigen Recognition • Immunocompetent T cells are activated when their surface receptors bind to a recognized antigen (nonself) • T cells must simultaneously recognize • Nonself (the antigen) • Self (an MHC protein of a body cell)

47. MHC Proteins • Two types of MHC proteins are important to T cell activation • Class I MHC proteins - displayed by all cells except RBCs • Class II MHC proteins – displayed by APCs (dendritic cells, macrophages and B cells) • Both types are synthesized at the ER and bind to peptide fragments

48. Class I MHC Proteins • Bind with fragment of a protein synthesized in the cell (endogenous antigen) • Endogenous antigen is a self-antigen in a normal cell; a nonself antigen in an infected or abnormal cell • Informs cytotoxic T cells of the presence of microorganisms hiding in cells (cytotoxic T cells ignore displayed self-antigens)

49. Cytoplasm of any tissue cell Cisternae ofendoplasmicreticulum (ER) Endogenous antigenpeptides enter ER viatransport protein. 2 Endogenousantigen is degradedby protease. 1 3 Endogenousantigen peptide isloaded onto classI MHC protein. Endogenous antigen—self-protein or foreign(viral or cancer) protein 4 Loaded MHC proteinmigrates in vesicle tothe plasma membrane,where it displays theantigenic peptide. Transportprotein(ATPase) Antigenic peptide Plasma membrane of a tissue cell Extracellular fluid (a) Endogenous antigens are processed and displayed on class I MHC of all cells. Figure 20.17a

50. Class II MHC Proteins • Bind with fragments of exogenous antigens that have been engulfed and broken down in a phagolysosome • Recognized by helper T cells